Discovery and application of new halogenases

新型卤化酶的发现及应用

• 批准号: 10589079
• 负责人: MICHELLE C CHANG
• 金额: $ 31.46万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589079
• 关键词: Active Sites; Alkynes; Amino Acids; Anabolism; Anions; Binding Proteins; Biochemical; Bioinformatics; Biological; Biology; Carbon; Catalysis; Cells; Chemicals; Chemistry; Complex; Conserved Sequence; Development; Electrons; Engineering; Enzymes; Evolution; Face; Family; Family member; Foundations; Generations; Geometry; Goals; Halogens; Health; Homologous Gene; Human; Hydrogen Bonding; Hydroxylation; In Vitro; Indole Alkaloids; Libraries; Link; Metabolic Biotransformation; Methodology; Modification; Molecular; Natural Products; Nature; Outcome; Pathway interactions; Peptides; Positioning Attribute; Production; Protein Engineering; Proteins; Public Health; Reaction; Ribosomes; Route; Source; Structure; Translations; catalyst; chemical function; design; functional group; halogenation; improved; in vivo; innovation; insight; interest; novel; restraint; scaffold; screening; small molecule; tool

Project Summary/Abstract The rapid and modular generation of molecular diversity is key to the search for new chemical functions. One particularly useful functional group is the halogen (X = Cl, Br, I), which enables many selective and effective downstream strategies for creating structural complexity. In this regard, halogenase enzymes have provided an important and complementary approach to synthetic catalysts for regio- and stereoselective introduction of a halogen substituent on a complex scaffold, which remains challenging to achieve. While many families of halogenases exist, the radical halogenases provide the greatest potential for reaction diversity, as they are competent to replace unactivated C-H bonds with a halogen unlike those that operate by electrophilic or nucleophilic mechanisms. However, the substrate scope of these enzymes has been limited to date to either protein-bound substrates or large late-stage natural product intermediates. Our group has discovered a new clade of radical halogenases capable of reacting with small molecule substrates. We now seek to take advantage of this discovery to develop new tools for in vitro and in vivo synthesis. Specific aims of this proposal include: (i) elucidating the structure and mechanism of these new radical halogenases, which will provide important insight into their engineering, (ii) investigating and engineering selectivity in halogenases, and (iii) developing applications for halogenases to produce new amino-acid based products.

项目总结/文摘